Neuropathology and Applied Neurobiology (2018), 44, 647–662 doi: 10.1111/nan.12513 Review: Revisiting the human cholinergic nucleus of the diagonal band of Broca A. K. L. Liu*,1 , E. J. Lim*,1, I. Ahmed†, R. C.-C. Chang‡,§, R. K. B. Pearce* and S. M. Gentleman* *Neuropathology Unit, Division of Brain Sciences, Department of Medicine, Imperial College London, †Department of Eye Pathology, Institute of Ophthalmology, University College London, London, UK, ‡Laboratory of Neurodegenerative Diseases, LKS Faculty of Medicine, School of Biomedical Sciences and §State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong A. K. L. Liu, E. J. Lim, I. Ahmed, R. C.-C. Chang, R. K. B. Pearce, S. M. Gentleman (2018) Neuropathology and Applied Neurobiology 44, 647–662 Revisiting the human cholinergic nucleus of the diagonal band of Broca Although the nucleus of the vertical limb of the diagonal from other neighbouring cholinergic cell groups for stan- band of Broca (nvlDBB) is the second largest cholinergic dardizing future clinicopathological work. Thorough nucleus in the basal forebrain, after the nucleus basalis review of the literature regarding neurodegenerative of Meynert, it has not generally been a focus for studies conditions reveals inconsistent results in terms of cholin- of neurodegenerative disorders. However, the nvlDBB ergic neuronal loss within the nvlDBB. This is likely to be has an important projection to the hippocampus and dis- due to the use of variable neuronal inclusion criteria and crete lesions of the rostral basal forebrain have been omission of cholinergic immunohistochemical markers. shown to disrupt retrieval memory function, a major def- Extrapolating from those studies showing a significant icit seen in patients with Lewy body disorders. One rea- nvlDBB neuronal loss in Lewy body dementia, we pro- son for its neglect is that the anatomical boundaries of pose an anatomical and functional connection between the nvlDBB are ill defined and this area of the brain is the cholinergic component of the nvlDBB (Ch2) and the not part of routine diagnostic sampling protocols. We CA2 subfield in the hippocampus which may be espe- have reviewed the history and anatomy of the nvlDBB cially vulnerable in Lewy body disorders. and now propose guidelines for distinguishing nvlDBB Keywords: Alzheimer’s disease, basal forebrain, cholinergic system, diagonal band of Broca, Lewy body dementia, Parkinson’s disease hypothesis’, a decreased level of acetylcholine in the Introduction cerebral cortex and hippocampus has been shown to Brain cholinergic neurotransmitter systems are instru- contribute to the cognitive decline seen in ageing and mental in many behavioural and cognitive processes Alzheimer’s disease (AD) [3]. The cholinergic innerva- including attention, learning, memory, arousal and tion of the neocortex and allocortex originates from the sleep [1,2]. As suggested in the ‘Cholinergic cholinergic basal forebrain complex. In humans, this complex is composed of interdigitating cell groups with approximately 200 000 neurons per hemisphere [4–6]. Correspondence: Alan K. L. Liu, Division of Brain Sciences, Using acetylcholinesterase (AChE) histochemistry and Department of Medicine, Imperial College London, 4/F, Burlington choline acetyltransferase (ChAT) immunohistochem- Danes Building, Du Cane Road, London W12 0NN, UK. Tel: +44 (0)2075946586; E-mail: [email protected] istry, Mesulam and colleagues introduced ‘Ch’ sectoral 1These authors contributed equally to this work. terminology to distinguish four groups of ChAT- © 2018 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd 647 on behalf of British Neuropathological Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 648 A. K. L. Liu et al. immunopositive neurons within the basal forebrain anatomical boundaries. Here, on the basis of a review based on morphology and rostral–caudal organization of the history and anatomy of the rostral basal fore- [7,8]. Ch1–Ch4 correspond to the cholinergic neurons brain, we provide recommendations for the visualiza- found in the medial septal nucleus (MSN), the nucleus of tion and sampling of the human nvlDBB. In addition, the vertical limb of the diagonal band of Broca (nvlDBB), we have reviewed clinicopathological studies involving the nucleus of the horizontal limb of the DBB (nhlDBB) the nvlDBB and postulate a role for cholinergic inputs and the nucleus basalis of Meynert (nbM), respectively. from this nucleus in the cognitive decline seen in PD Retrograde tracer experiments using horseradish peroxi- and AD. dase in nonhuman primates showed that Ch1 and Ch2 provide cholinergic efferents to the hippocampal com- Historical perspectives plex, Ch3 to the olfactory bulb and Ch4 to the neocortex and amygdala. Coining the term diagonal band (of Broca) With over 90% of its magnocellular neurons being cholinergic, the nbM is the largest and most well- In a series of monographs published in the 1870s and studied cell group within the cholinergic basal fore- 1880s comparing the great limbic lobes (Le grand lobe brain. Degeneration of the nbM has been correlated limbique) in the brains of different mammalian species with the presence of dementia in neurological condi- [10–12], French physician and anatomist Pierre Paul tions and we have previously hypothesized that subre- Broca defined a ‘diagonal band’ (La bandelette diagonale) gions of the nbM are differentially affected in within a quadrilateral space located directly superior to Parkinson’s disease (PD) and AD [9]. By contrast, the optic chiasm (Figure 1). He described the band as pathology within the nvlDBB, which is the second lar- seen from the inferior surface of the brain to run diago- gest cholinergic group in the basal forebrain and with nally from the anterior and ‘outermost’ portion of the up to 70% of neurons being ChAT-positive, is much ‘hippocampal lobe’ to the root of the olfactory tract, less well characterized in neurodegenerative conditions. joining the medial olfactory striae at the midline. On Given that hippocampal pathology is implicated in macrodissection, Broca related that the diagonal band many dementing disorders and with the hippocampus passes in front of the optic chiasm and descends into receiving extensive innervation from the nvlDBB, it is the hemisphere. It then travels anterior to the anterior important now to revisit this relatively neglected commissure and the medial septal fibres towards the cholinergic cell group. Furthermore, there is a signifi- genu of the corpus callosum. At a coronal level, this cant overlap between the nvlDBB and adjacent cholin- can be identified clearly as a white-matter bundle med- ergic loci, so there is as yet no clear consensus on its ial to the nucleus accumbens of the basal ganglia Figure 1. An illustration of the diagonal band (d–d0) in the human brain seen from the inferior surface, with the optic tract retracted, as described in Broca’s monograph in 1888 [12] (left). Coronal section at a level approximately 1.5 cm anterior to the mammillary bodies (red dashed line) revealed the extent of the diagonal band (black arrows) on both sides of the hemisphere, medial to the basal ganglia (right). Cd, caudate; IC, internal capsule; LV, lateral ventricle; nAcc, nucleus accumbens; PO, paraolfactory area; Pt, putamen. © 2018 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd NAN 2018; 44: 647–662 on behalf of British Neuropathological Society Nucleus of the diagonal band of Broca 649 (Figure 1). Further afield, the course of the diagonal authors noted the important distinction that the nDBB band became difficult to follow, but Broca postulated is a ‘distinct band of deeply staining cells’ embedded that most of the fibres travel behind the corpus callo- within and following the course of the DBB. sum and establish a direct connection between this lobe and the hippocampus. This projection is similar to the Subdivisions and the two ‘limbs’ of the DBB septal arcuate fibres described by Karl Friedrich Bur- dach in 1822 which is probably identical to the tract Building on Papez’s study, Herald Brockhaus was first described by Broca [13]. Sir Grafton Elliot Smith, an to extensively characterize the nDBB (die kerngruppe Australian-British anatomist, acknowledged Broca’s des diagonalen Bandes) in humans in his comparative work and introduced the term DBB to the English study of the basal forebrain cell groups (Basalkernkom- literature [14]. plex) in primates [21]. Based on the cell morphology, location and orientation, Brockhaus subdivided the nDBB rostrocaudally into the nucleus diagonalis septalis, Defining the ‘nucleus’ of the DBB angularis and ventralis. Subsequently, in a study of the Previously mistaken as the medial paraolfactory septum in the human brain, Andy and Stephan nucleus, the nucleus of the DBB (nDBB) was first divided the nDBB into ‘tubercular’ and ‘septal’ parts, described in the brains of box turtles (Cistudo Carolina) with the septal part located against the medial sep- as a cell mass extending from just rostral to the ante- tum, and the tubercular part located against the ven- rior commissure decussation down to the optic chiasm tral aspect (olfactory tubercle) of the brain [22]. In and caudal to the basolateral surface of the amygdaloid both subdivision schemes, the borders between subdi- complex [15]. Subsequently, the nDBB was described in visions were arbitrarily defined and lack any func- alligators (Alligator mississippiensis) [16], opossums tional significance. (Didelphis virginiana) [17,18], rabbits [17] and rats [19]. Experimental lesioning of the fimbria-fornix in rats, The nDBB was also described in the brain of an 8- rabbits and the macaque monkey has demonstrated month-old human foetus in a comparative neu- retrograde degeneration of the MSN and the nDBB, but roanatomy study [17]. Johnson reported that the nDBB limited to the vertical limb of the nucleus [23].